ABSTRACT Zika virus (ZIKV) is a member of the genus Flavivirus, and transmitted by Aedes sp. mosquitoes. There are three genetic lineages of ZIKV: East Africa, West Africa, and Asia. Until recently Zika fever has normally been considered a rare, mild febrile disease, but reports since 2012 indicate potentially severe complications associated with ZIKV infection, including microcephaly and Guillain-Barr syndrome, associated with Asian lineage viruses. Since 2015, ZIKV has become epidemic in the Americas with reports of clinical cases in at least 37 countries in the Americas. There is a clear need for a vaccine. However, there have been very few studies on ZIKV until 2015 and vaccine development is starting from ground zero. An important step in the vaccine development pipeline is preclinical development where a candidate vaccine is evaluated for safety and immunogenicity in animal models prior to clinical evaluation. A number of candidate Zika vaccines are in development and it will be critical to evaluate them in animal models to aid down-selection for those that will be tested in humans. Very recently, there have been a number of papers describing either mouse or non-human primate (NHP) models for ZIKV. The NHP models are non-lethal and demonstrate viremia but it is transient and low. The mouse models result in a lethal infection but only cause clinical disease in interferon receptor ?? (A129) and ??? (AG129) knockout mice. However, there are questions about the applicability of such mouse models to vaccine development. The objective of this exploratory R21 application is to evaluate whether or not A129 and/or AG129 mouse models can be used to evaluate candidate ZIKV vaccines and by benchmarking against a licensed flavivirus vaccine, namely Japanese encephalitis (JE), as there are commercial live attenuated and inactivated vaccines that utilize mouse models for potency as part of the evaluation criteria for administration to humans. In particular, a neutralizing antibody titer of 1 in 10 is the correlate of protection of JE vaccines. Specific Aim 1a will examine whether or not live and inactivated JE vaccines will induce protective immunity and neutralizing antibodies in wild-type 129, A129 and AG129 mice. Specific Aim 1b will examine whether or not candidate recombinant envelope protein, inactivated ZIKV and attenuated ZIKV vaccines will induce protective immunity and neutralizing antibodies in wild-type 129, A129 and AG129 mice. Specific Aim 2 will protection of mice against ZIKV challenge by passive administration of neutralizing antibodies. Comparison of the results from licensed JE vaccine with candidate ZIKV vaccines will enable evaluation of A129 and/or AG129 mice as a preclinical model for ZIKV vaccine development.